Pulmonary alveolar proteinosis (PAP) is characterized by accumulation of surfactant in pulmonary alveoli resulting in respiratory failure and increased infection risk in most patients due to the defective granulocyte/macrophage-colony stimulating factor (GM-CSF) signaling. Disruption is caused by GM-CSF autoantibodies (GMAbs) in autoimmune PAP (aPAP) accounting for 90% of cases or by mutations in the GM-CSF receptor a or p genes [CSF2RA, CSF2RB] in hereditary PAP (hPAP) in 5% or less. Historically, a diagnosis of PAP has required a lung biopsy. However, while a lung biopsy can determine if PAP is present, it cannot identify the disease responsible and therefore does not inform prognosis or therapeutic alternatives. This is a critical limitation since therapeutic options, treatment responses, and prognosis vary widely depending on which disease caused PAP. We developed a set of blood tests that can diagnose aPAP and hPAP with high specificity and sensitivity. We recently developed an approach using a dried blood spot card (DBSC) for blood collection, which patients can use to collect their own samples and send them by mail in an envelope to the test center. While a pivotal study has demonstrated that inhaled GM-CSF therapy of aPAP is effective, further studies are needed to optimize the protocol in a larger group of patients. Importantly, to translate these novel findings into clinical practice, it will be necessary to organize the PAP patient community and establish the natural history of PAP. The long term goal of this research is to improve the diagnosis and therapy of PAP. The objectives of this application are to evaluate blood-based diagnostics, identify novel disease mechanisms and HLA associations. measure the incidence and prevalence of PAP in the United States (US), and define the natural history of aPAP and hPAP. Our central hypothesis is that an observational study with cross-sectional and longitudinal components will inform the epidemiology, pathogenesis, and natural history of PAP and will facilitate the conduct of planned, future therapeutic trials in people with PAP. This hypothesis will be addressed in the following Aims. In Aim 1, we will optimize and validate DBSC testing for the diagnosis of aPAP and study the epidemiology of PAP in the US. In Aim 2, we will identify human alleles associated with an increased risk of developing PAP. In Aim 3, we will utilize DSBC testing to conduct prospective, longitudinal observation study to evaluate the natural history of PAP. Anticipated results will validate novel blood-tests for the diagnosis of PAP, and identify new mutation(s) as a novel cause of hPAP, define the incidence and prevalence of PAP, potential HLA allele-specific associations of aPAP, and comprise the first prospective natural history study of PAP. This project will impact the field by transforming how PAP is diagnosed: using a simple, inexpensive, self-administered test that improves access for patients in remote locations, and by organizing the patient community for planned therapeutic trials. Finally, we will help organize the PAP patient community for planned therapeutic trials by creating a National PAP registry using inexpensive methods integrated with our CCTST.